The TRPM6 Kinase Domain Determines the Mg·ATP Sensitivity of TRPM7/M6 Heteromeric Ion Channels

Background: TRPM6 and TRPM7 combine ion channel and -kinase functions. Results: ATP inhibits TRPM7 but not TRPM6 or heteromeric TRPM6/M7 channels. Disruption of phosphorylation activity of TRPM6 kinase re-establishes ATP sensitivity to heteromeric channels. Conclusion: TRPM6 uncouples heteromeric channels from cellular energy levels. Significance: The altered characteristics of TRPM6/M7 compared with homomeric TRPM7 may enhance Ca2+ and Mg2+ transport in tissues co-expressing both proteins.The transient receptor potential melastatin member 7 (TRPM7) and member 6 (TRPM6) are divalent cation channel kinases essential for magnesium (Mg2+) homeostasis in vertebrates. It remains unclear how TRPM6 affects divalent cation transport and whether this involves functional homomeric TRPM6 plasma membrane channels or heteromeric channel assemblies with TRPM7. We show that homomeric TRPM6 is highly sensitive to intracellular free Mg2+ and therefore unlikely to be active at physiological levels of [Mg2+](i). Co-expression of TRPM7 and TRPM6 produces heteromeric TRPM7/M6 channels with altered pharmacology and sensitivity to intracellular MgATP compared with homomeric TRPM7. Strikingly, the activity of heteromeric TRPM7/M6 channels is independent of intracellular MgATP concentrations, essentially uncoupling channel activity from cellular energy status. Disruption of TRPM6 kinase phosphorylation activity re-introduces MgATP sensitivity to the heteromeric channel similar to that of TRPM7. Thus, TRPM6 modulates the functionality of TRPM7, and the TRPM6 kinase plays a critical role in tuning the phenotype of the TRPM7M6 channel complex.